19-4180839-C-T

Position:

• chr19-4180839-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001321064.2(SIRT6):​c.-80G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.926 in 1,613,490 control chromosomes in the GnomAD database, including 695,447 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.92 (64372 hom., cov: 32)
  • Exomes 𝑓: 0.93 (631075 hom.)
• Consequence: SIRT6 NM_001321064.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19

Genes affected

SIRT6 (HGNC:14934): (sirtuin 6) This gene encodes a member of the sirtuin family of NAD-dependent enzymes that are implicated in cellular stress resistance, genomic stability, aging and energy homeostasis. The encoded protein is localized to the nucleus, exhibits ADP-ribosyl transferase and histone deacetylase activities, and plays a role in DNA repair, maintenance of telomeric chromatin, inflammation, lipid and glucose metabolism. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

SIRT6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5308162E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.942 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIRT6	NM_016539.4	c.137G>A	p.Ser46Asn	missense_variant	2/8	ENST00000337491.7	NP_057623.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIRT6	ENST00000337491.7	c.137G>A	p.Ser46Asn	missense_variant	2/8	1	NM_016539.4	ENSP00000337332.1

Frequencies

GnomAD3 genomes AF: 0.918 AC: 139622 AN: 152102 Hom.: 64309 Cov.: 32

Gnomad AFR AF: 0.934

Gnomad AMI AF: 0.896

Gnomad AMR AF: 0.839

Gnomad ASJ AF: 0.941

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.825

Gnomad FIN AF: 0.910

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.948

Gnomad OTH AF: 0.905

GnomAD3 exomes AF: 0.885 AC: 221005 AN: 249774 Hom.: 98827 AF XY: 0.888 AC XY: 120191 AN XY: 135320

Gnomad AFR exome AF: 0.936

Gnomad AMR exome AF: 0.752

Gnomad ASJ exome AF: 0.947

Gnomad EAS exome AF: 0.728

Gnomad SAS exome AF: 0.831

Gnomad FIN exome AF: 0.910

Gnomad NFE exome AF: 0.946

Gnomad OTH exome AF: 0.904

GnomAD4 exome AF: 0.927 AC: 1355088 AN: 1461270 Hom.: 631075 Cov.: 57 AF XY: 0.925 AC XY: 672519 AN XY: 726944

Gnomad4 AFR exome AF: 0.933

Gnomad4 AMR exome AF: 0.765

Gnomad4 ASJ exome AF: 0.948

Gnomad4 EAS exome AF: 0.698

Gnomad4 SAS exome AF: 0.836

Gnomad4 FIN exome AF: 0.911

Gnomad4 NFE exome AF: 0.950

Gnomad4 OTH exome AF: 0.920

GnomAD4 genome AF: 0.918 AC: 139743 AN: 152220 Hom.: 64372 Cov.: 32 AF XY: 0.914 AC XY: 68030 AN XY: 74418

Gnomad4 AFR AF: 0.934

Gnomad4 AMR AF: 0.839

Gnomad4 ASJ AF: 0.941

Gnomad4 EAS AF: 0.719

Gnomad4 SAS AF: 0.826

Gnomad4 FIN AF: 0.910

Gnomad4 NFE AF: 0.948

Gnomad4 OTH AF: 0.907

Alfa AF: 0.938 Hom.: 115142

Bravo AF: 0.912

TwinsUK AF: 0.954 AC: 3536

ALSPAC AF: 0.954 AC: 3676

ESP6500AA AF: 0.936 AC: 4123

ESP6500EA AF: 0.947 AC: 8147

ExAC AF: 0.890 AC: 107986

Asia WGS AF: 0.780 AC: 2714 AN: 3478

EpiCase AF: 0.950

EpiControl AF: 0.948

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.83
DEOGEN2	Benign	0.0040	T;.;T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.023	T;T;T;T;T
MetaRNN	Benign	0.0000015	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.50	.;N;N;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.4	.;N;N;.;.
REVEL	Benign	0.042
Sift	Benign	0.41	.;T;T;.;.
Sift4G	Benign	0.17	T;T;T;.;T
Polyphen		0.0	.;B;B;.;.
Vest4		0.046
MPC		0.34
ClinPred		0.00046	T
GERP RS		1.5
Varity_R		0.077
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs352493; hg19: chr19-4180836;